The immune system functions to protect individuals from infective agents, e.g., bacteria, multi-cellular organisms, and viruses, as well as from cancers. This system includes several types of lymphoid and myeloid cells such as monocytes, macrophages, dendritic cells (DCs), eosinophils, T cells, B cells, and neutrophils. These lymphoid and myeloid cells often produce signaling proteins known as cytokines. The immune response includes inflammation, i.e., the accumulation of immune cells systemically or in a particular location of the body. In response to an infective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate immune cell proliferation, development, differentiation, or migration. Immune response can produce pathological consequences, e.g., when it involves excessive inflammation, as in the autoimmune disorders (see, e.g., Abbas et al. (eds.) (2000) Cellular and Molecular Immunology, W.B. Saunders Co., Philadelphia, Pa.; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, Calif.; von Andrian and Mackay (2000) New Engl. J. Med. 343:1020-1034; Davidson and Diamond (2001) New Engl. J. Med. 345:340-350).
Myeloid cells (i.e., macrophages, dendritic cells (DC), neutrophils, mast cells, and eosinophils) play important roles in maintaining chronic inflammation (Kinne, R. W., et al (2000) Arthritis Res. 2:189-202; Kiefer, R. B. et al (2001) Progr. Neurobiol. 64:109-127; O'Shea, J. J. et al (2002) Nat. Rev. Immunol. 2:37-45; Hamid, Q. et al (2003) J. Allergy Clin. Immunol. 111: S5-S12; Liu, H. et al (2004) Rheum Dis. Clin. North Am. 30:19-39). They can be regulated through cell-cell interactions that trigger matched sets of activating in inhibitory receptors, in addition to being regulated by secreted factors (Barclay, A. N. et al (2002) Trends in Immunol. 23: 285-290). The regulation of myeloid cell activity by direct cell-cell contact allows a more localized control than that mediated by cytokines. The CD200-CD200R interaction also provides a cell-cell contact regulatory interaction for myeloid cells. The widely expressed glycoprotein CD200 is closely related structurally to the T cell costimulatory molecules CD80 and CD86 and is genetically linked to them on human chromosome 3 and mouse chromosome 16 (McCaughan, G. W. (1987) Immunogenetics 25:133-135; Borriello, F. et al (1998) Mamm. Genome 9:114-118). Structurally, CD200 contains two Ig superfamily (IgSF) domains in a typical V/C2 arrangement (Clark, M. J. et al (1985) EMBO J 4:113-118).
The CD200R is expressed at the surface of human and mouse myeloid cells, such as macrophages, DCs, neutrophils, and mast cells, and also on T cells (Wright, G. J. et al (2000) Immunity 12:233-242; Wright, G. J. et al (2003) J. Immunol. 171:3034-3046). CD200R is structurally related to CD200, located on the same chromosome, the genes probably evolved by gene duplication (Wright, G. J. et al (2003) J. Immunol. 171:3034-3046). However, CD200R is distinct from CD200 and displays a longer cytoplasmic tail containing three conserved tyrosine residues, one of which is contained with an NPXY motif (Wright, G. J. et al (2000) Immunity 12:233-242; Wright, G. J. et al (2003) J. Immunol. 171:3034-3046). Upon ligand or agonist antibody binding, CD200R is phosphorylated on the tyrosine of the NPXY motif and subsequently binds adapter proteins Dok1 and Dok2. Phosphorylation of these adapter proteins recruits SHIP and RasGAP, which subsequently inhibits the Ras/MAPK activation pathways (Zhang, S. et al. 2004, J. Immunol. 173:6786-6793).
The CD200 receptor (CD200R) has now been cloned from a variety of species including rats, mice, humans and several non-human primates. CD200R is located on human chromosome 3q12-13 and on mouse chromosome 16 and both human and mouse CD200R show high degrees of similarities in sequence and structure (Wright, G. J. et al (2003) J. Immunol. 171:3034-3046). In addition to CD200R, four related genes have been identified in the mouse (Wright, G. J. et al (2003) J. Immunol. 171:3034-3046). These genes were termed CD200RL (CD200R-like), and have been shown to associate with the activating adaptor protein, DAP12 (Lanier, L. L. (1998) Nature 39:703). DAP12 is required for cell surface expression of these receptors and for signal transduction. Dap12 is a potent activating adaptor protein that contains a classic immune tyrosine-based activation motif (ITAM), and thus the mouse CD200RL genes are myeloid activating genes. Mouse mast cells express these activating CD200RL receptors and they can be triggered using receptor specific antibodies to generate potent degranulation responses similar in magnitude to that observed with FcξRI activation. Although these additional CD200R family member genes have been termed CD200R-like based on sequence homology to the extracellular domain of CD200R, they do not bind CD200 and at present the ligand(s) for these additional receptors remains unknown (Hatherly D. et al (2005) J Immunol 175(4):2469-74). In addition some outbreed strains of mice express CD200RLe, a CD200R family member with homology to CD200R (Hatherly D. et al (2005) Journal of Immunology 175: 2469-2474). In contrast to the mouse CD200R family, the human genome showed only two CD200R family members: CD200R and CD200RLa (Wright, G. J. et al (2003) J. Immunol. 171:3034-3046)
The need exists for agonists of the human inhibitory CD200R, such as anti-human inhibitory CD200R monoclonal antibodies, for use in treatment of human disorders, such as inflammatory or autoimmune disorders. Such agonists will preferably exhibit low immunogenicity in human subjects, allowing for repeated administration without adverse immune responses.